tbuckley/cabot-search huggingface dataset:
PATH-25. LEPTOMENINGEAL, DURAL, AND EXTRACRANIAL METASTASIS OCCUR IN DIVERSE TYPES OF ADULT HIGH-GRADE GLIOMA
Authors: Sarah Travers, B K Kleinschmidt-DeMasters, D Ryan Ormond
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Leptomeningeal and extracranial metastases in adult high-grade gliomas are being increasingly recognized as critical issues. Our group has a longstanding interest in this issue, having published multiple examples in 2015 (PMID: 26308254) and 1996 (8617464). We now update our experience, illustrating that dissemination can occur in diverse types of high-grade gliomas, even those with purportedly more favorable prognoses. METHODS Search of records, 2018-present, to identify patients with leptomeningeal, dural, and/or extracranial spread clinically recognized prior to patient demise. RESULTS Leptomeningeal dissemination was identified in 6 patients: one astrocytoma (frontal lobe, IDH1 R132H+, metastatic to 3-levels spinal cord), a second astrocytoma (frontal lobe, IDH1 R132H+, metastatic to spinal cord with intracranial dissemination), one glioblastoma, small cell type (PIK3CA, CDH1, TP53 mutations, temporal lobe metastatic to cervical cord), one high-grade glioma with piloid features (HGAP, metastatic at presentation; BRAF-mutant, classified by DNA methylation (NIH)) and one high-grade glioma with no match to DNA methylation class (metastatic at presentation, NIH). There were three additional patients: one patient with glioblastoma with FGFR: TACC3 fusion with short-interval dural and cervical lymph node metastases (in Press), one patient with glioblastoma with EGFR amplification and dural invasion and one patient with glioblastoma with massive dural spread and bony invasion at presentation. CONCLUSION Although these new 9 individual cases provide no insights into the epidemiology of GBM leptomeningeal, dural and extracranial metastases, our single-institution series, using updated molecular classifications not always available in retrospective studies, shows that dissemination can occur in any, and all, types of adult high-grade gliomas. We put this cohort in perspective with our experience with dissemination in other low and high-grade tumor types: anaplastic myxopapillary ependymomas (30417460), H3 K27M-altered high-grade gliomas (29393845), pineal parenchymal tumors of intermediate differentiation (34418607), myxoid glioneuronal tumor, PDGFRA-mutant (34297434) and spinal cord gangliogliomas (25015869).
INNV-16. SPINAL POST-TREATMENT SURVEILLANCE IN MEDULLOBLASTOMA – A SYSTEMATIC REVIEW OF THE LITERATURE AND CLINICAL TRIALS
Authors: Christopher Park, Roger Packer, Brian Rood, Lindsay Kilburn, Miriam Bornhorst, Christopher Rossi, Adriana Fonseca, Eugene Hwang
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Monitoring for dissemination in medulloblastoma involves spinal MRIs (sMRIs) and lumbar punctures (LPs). The frequency and duration of these studies vary depending on risk of dissemination; general practice varies between and within institutions. Our goal is to review the current practice in post-treatment monitoring via examination of published data, clinical trial standards, and expert practice. METHODS We reviewed the available literature and accessible clinical trial protocols. Using PRISMA guidelines, we conducted searches of Ovid MEDLINE, Embase, and PubMed to identify studies which detailed relapse rates and patterns, and recommended practice for patients with medulloblastoma aged 3-21 years. Eligible studies from 1990 to present were included. RESULTS Thirteen multi-institutional clinical trials from North America and Europe were analyzed for frequency of post-therapy surveillance with LPs/sMRIs. Several studies (n=8) recommend LPs/sMRIs every 3-6 months in standard risk and every 3 months in high risk disease for two years when initially completing therapy, and then often diverge in frequency after 2 years. Some studies (n=5) did not include post-treatment recommendations. Cumulative data on relapse from available clinical trial reports and single institution studies (n=673 relapses) demonstrated local failure rate of 18.4%, distant failure of 49.1%, and combined distant and local failure of 32.5%. Spine-only relapses were reported to occur in approximately 13-20%, with one small study reporting spine-only relapse rate of 37.5%. DISCUSSION Patterns of recurrence in medulloblastoma have shifted over time as therapeutic approaches have evolved, including more spinal-only recurrences. Standardized guidance regarding surveillance could have significant impact on clinical detection and streamline management to minimize unnecessary examinations. Early detection of recurrent disease could optimize treatment options for providers and families, whether focusing on curative approaches or quality of life.
EXTH-99. SYSTEMIC AND BRAIN PHARMACOKINETICS OF A GABAA RECEPTOR AGONIST, AMLAL-101, AS AN INVESTIGATIONAL THERAPEUTIC FOR THE TREATMENT OF PRIMARY AND METASTATIC BRAIN CANCERS
Authors: Aniruddha Karve, Taukir Ahmed, Janki Desai, Debanjan Bhattacharya, Donatien Kamdem Toukam, Sidharth Gadgil, Merissa Pemberton, David Plas, Gary Gudelsky, Larry Sallans, James Cook, Pankaj Desai, Daniel Pomeranz Krummel, Soma Sengupta
Journal: Neuro-Oncology (2022)

Abstract PURPOSE AMLAL-101 is a novel agent which preferentially targets α3, α5 subtypes of ɣ-amino butyric acid receptors and shows anti-tumor activity against disparate cancer types. AMLAL-101 is being advanced as an ‘add-on’ to potentiate treatment of primary and metastatic brain cancers. However, AMLAL-101 must penetrate the blood-brain barrier (BBB) and show sufficient brain retention. The primary purpose of this study was to determine the plasma pharmacokinetics (PK) and quantitative estimate of the BBB permeability of AMLAL-101. METHODS We performed intracranial microdialysis, employing jugular vein cannulated Sprague-Dawley rats which facilitated simultaneous serial blood and brain extracellular fluid (ECF) sampling. AMLAL-101 was injected i.p. at 5 mg/kg and serial blood and brain ECF samples collected up to 10 h post-dosing. Plasma and ECF samples were analyzed by LC/MS-MS and plasma and ECF concentration vs time PK profiles determined. In vivo recovery analysis was performed using retrodialysis and rapid equilibrium dialysis employed to determine the extent of protein binding. RESULTS AMLAL-101 plasma protein binding was 85% and in vivo recovery from ECF was 25%. AMLAL-101 peak concentration (Cmax) in plasma and brain ECF were 15 µM and 13.8 µM, respectively. The plasma and brain ECF area under the concentration (AUC0-10) were 27.5 h.µg/mL and 24.10 h.µg/mL, respectively. The brain partitioning of unbound AMLAL-101 (Kp,uu; determined either as a ratio of brain ECF Cmax:unbound plasma Cmax or brain ECF AUC: unbound plasma AUC), were 6.13 and 4.13, respectively. The elimination half-life of AMLAL-101 was 3 h for both brain ECF and plasma. CONCLUSIONS These results suggest that AMLAL-101 has the requisite BBB permeability required for brain cancer therapeutics. AMLAL-101 shows significant brain retention when compared to a chemically similar agent that does not show anti-cancer activity, which may contribute to efficacy of AMLAL-101 as an anti-tumor agent for treatment of brain cancers.
NIMG-19. IMAGE-BASED MODELING MAP OF EDEMA IS CORRELATED WITH MULTIPLE BLOOD-BRAIN-BARRIER PERMEABILITY RELEVANT TRANSCRIPTOMIC MARKERS IN BRAIN TUMOR PATIENTS
Authors: Pamela Jackson, Sara Ranjbar, Lee Curtin, Kamila Bond, Kyle Singleton, Andrea Hawkins-Daarud, Jing Li, Peter Canoll, Leland Hu, Nhan Tran, Kristin Swanson
Journal: Neuro-Oncology (2022)

Abstract Brain tumor associated edema is a significant cause of patient morbidity and mortality often requiring continual treatment with differing levels of success across patients. Edema is a broad term that can indicate increased local water as well as diffusely infiltrating tumor cells. Edema is visualized as hyperintense regions on T2-weighted (T2W) magnetic resonance imaging (MRI) and is typically associated with blood-brain barrier (BBB) breakdown and tumor aggressiveness. Understanding the molecular mechanisms driving imaging patterns of “edema” could provide insights into clinical imaging interpretation. We have an ongoing image-guided biopsy study that allows us to link biopsy molecular markers with locoregional MRI patterns of edema. Further, we previously developed a physics-based method to estimate edema abundance (i.e., edema map) from T2W MRIs. Our goal was to identify connections between BBB-associated molecular factors and edema abundance in brain tumors. Our cohort included 38 patients (female: 15, male: 23) with 129 image-guided biopsies (female: 62, male: 67). We correlated image-localized edema map values with the mean transcriptional frequency for 57 genes related to BBB function. Additionally, we examined correlations separately according to patient reported sex (i.e., male and female) and imaging phenotype (i.e., ENH: enhancing and NE: non-enhancing). We utilized multiple comparisons corrections with a 5% false discovery rate to determine significance. For the overall cohort, we observed significant positive correlations for the HIF1A (p&amp;lt; 0.001) and SOX2 markers with edema. For NE samples, significant correlations included APOE (p=0.001), HIF1A (p&amp;lt; 0.001), PIK3CA (p&amp;lt; 0.001), PTCH1 (p&amp;lt; 0.001), and SOX2 (p&amp;lt; 0.001). Amongst female samples, a significant correlation with PTCH1 (p=0.002) was observed. There were no significant correlations noted for male and enhancing sub-cohorts. Significant correlations between molecular markers of BBB and edema map values could lead to clinical biomarkers for edema or tumor aggressiveness.
NIMG-20. INCORPORATION OF AI-BASED AUTOSEGMENTATION AND CLASSIFICATION INTO NEURORADIOLOGY WORKFLOW: PACS-BASED AI TO BUILD YALE GLIOMA DATASET
Authors: Jan Lost, Niklas Tillmans, Sara Merkaj, Marc von Reppert, MingDe Lin, Khaled Bousabarah, Anita Huttner, Sanjay Aneja, Antonio Omuro, Mariam Aboian, Arman Avesta
Journal: Neuro-Oncology (2022)

Abstract PURPOSE Translation of AI algorithms into clinical practice is significantly limited by lack of large individual hospital-based datasets with expert annotations. Current methods for generation of annotated imaging data are significantly limited due to inefficient imaging data transfer, complicated annotation software, and time required for experts to generate ground truth information. We incorporated AI tools for auto-segmentation of gliomas into PACS that is used at our institution for reading clinical studies and developed a workflow for annotation of images and development of volumetric segmentations in neuroradiology clinical workflow. Material: 1990 patients from Yale Radiation Oncology Registry (2012-2019) were identified. Segmentations were performed using a UNETR algorithm trained on BRaTS 2021 and an internal dataset of manually segmented tumors. Segmentations were validated by a board-certified neuro-radiologist and natively embedded PyRadiomics in PACS was used for feature extraction. RESULTS In 7 Months (05/2021 - 08/2021, 03/2022 - 05/2022) segmentations and annotations were performed in 835 patients (322 female, 467 male, 46 unknown, mean age 53 yrs). Dataset includes 275 Grade 4 Gliomas (54 Grade 3, 100 Grade 2, 31 Grade 1, 375 unknown). Molecular subtypes include IDH (113 mutated, 498 wildtype, 2 Equivocal, 222 unknown), 1p/19q (87 deleted or co-deleted, 122 intact, 626 unknown), MGMT promotor (182 methylated, 95 partially methylated, 275 unmethylated, 283 unknown), EGFR (76 amplified, 177 not amplified, 582 unknown), ATRX (40 mutated, 157 retained, 638 unknown), Ki-67 (616 known, 219 unknown) and p53 (549 known, 286 unknown). Classification of gliomas between grade 3/4 and grade 1/2, yielded AUC of 0.85. CONCLUSION We developed a method for incorporation of volumetric segmentation, feature extraction, and classification that is easily incorporated into neuroradiology workflow. These tools allowed us to annotate over 100 gliomas per month, thus establishing a proof of concept for rapid development of annotated imaging database for AI applications.
NCMP-12. SECONDARY VERSUS RECURRENT CENTRAL NERVOUS SYSTEM LYMPHOMA - SIMILAR OR DIFFERENT?
Authors: Danielle Bazer, Ewa Zabrocka, Matthew Orwitz, Agnieszka Kowalska
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Although rare, primary central nervous system lymphoma (PCNSL) affects 0.5 per 100,000 individuals. It is estimated that 5% of cases will develop into secondary central nervous system lymphoma (SCNSL) and 2-5% will evolve into recurrent CNS lymphoma (RPCNSL) with the diffuse large B-cell lymphoma (DLBCL) variant of RPCNSL. METHODS This is a retrospective study; data obtained via chart review. RESULTS We compared 3 patients with RPCNSL to 3 patients with SCNSL. All patients were EBV and HIV negative, DLBCL variant. The average age of diagnosis with the first malignancy with RCNSL was 62.7 years old and age at recurrence was 66.7. With SCNSL, the initial age of diagnosis averaged to 72.7 years old and with secondary presentation at an average age of 76. Initial PCNSL treatments for RPCSNL were steroids, RCHOP with radiation, and DeAngelis Protocol. Initial malignancies for patients with SCNSL were renal cell carcinoma in 2 patients and atypical chronic lymphocytic leukemia variant with 17p deletion. All patients with RPCNSL presented with altered mental status and 2/3 SCNSL patients were altered upon presentation; 1 SCNSL patient was asymptomatic. The lesions within the RPCNSL cohort were all single lesions, localized to the frontal and temporal lobes. Within the SCNSL cohort, 2/3 patients had multiple lesions, whereas 1 patient had single lesions. All of the RPCNSL patients were ultimately on palliative care. SCNSL 2/3 were lost to follow-up and 1/3 elected to proceed with further treatment. CONCLUSION Although differing in etiology, there are shared features among SCNSL and RPCNSL. Most relapses are in the central nervous system, a small number of relapses are isolated systemic relapses, and clinical symptoms occur early and vary. Treatment is similar for both, although the prognosis for RPCNSL is very poor.
DNAR-10. THE EFFICACY OF TEMOZOLOMIDE AND LOMUSTINE IN GLIOBLASTOMA CELL LINES MAY BE ENHANCED BY CONCOMITANT TREATMENT WITH TUMOR TREATING FIELDS (TTFIELDS)
Authors: Hila Fishman, Roni Monin, Eyal Dor-On, Adi Haber, Moshe Giladi, Uri Weinberg, Yoram Palti
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Temozolomide (TMZ) is part of the standard of care for patients with newly diagnosed GBM (ndGBM). Expression of the enzyme MGMT involved in TMZ-induced DNA damage repair is associated with irresponsiveness of some patients to TMZ. The addition of lomustine (CCNU) to TMZ demonstrated clinical benefit in patients with ndGBM. Tumor Treating Fields (TTFields) are electric fields that display anti-mitotic effects and lower expression levels of proteins from the FA-BRCA DNA repair pathway in cancerous cells. TTFields therapy concomitant with TMZ is approved for the treatment of ndGBM. The aim of the current study was to examine the effect of TTFields in conjunction with TMZ and CCNU in GBM cells. Human GBM cell lines with different MGMT expression levels (U-87 MG, LN229, U118, and LN18) were treated with TTFields (0.83 V/cm RMS, 200 kHz) concomitant with TMZ and/or CCNU. Cell counts, colony formation, and apoptosis were used to measure effectiveness. The effect of TTFields with concomitant TMZ was additive in all cell lines, regardless of MGMT expression levels. TTFields in conjunction with CCNU displayed an additive effect in cell lines with high MGMT expression, and tendency to synergism in cell lines with low or no MGMT expression. TTFields concurrent with both TMZ and CCNU further increased treatment efficacy. Mechanistically, TTFields elevated the levels of DNA double strand breaks and lowered expression of FA-BRCA pathway proteins, as detected by fluorescence microscopy and western blot, respectively. The involvement of the FA-BRCA pathway in repair of DNA damage induced by CCNU and the BRCAness state induced by TTFields rationalize the synergy seen for TTFields with CCNU, especially in cells absent of MGMT. The results suggest a potential benefit of TTFields therapy concomitant with TMZ/CCNU for the treatment of GBM.
NIMG-98. IDENTIFYING PATTERNS OF FAILURE AFTER INITIAL THERAPY IN PRIMARY CNS LYMPHOMA IN A LARGE PATIENT COHORT
Authors: Kathryn Tringale, Joachim Yahalom, Michael Scordo, Behroze Vachha, Lauren Schaff, Christian Grommes, Brandon Imber
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Treatment of primary CNS lymphoma (PCNSL) has rapidly evolved, emphasizing improved efficacy while reducing neurotoxicity. PCNSL has historically been considered a multifocal disease and many patients relapse after first-line therapy. We evaluated relapse patterns in a large cohort of contemporarily treated patients. METHODS Consecutive PCNSL patients treated at MSKCC between 1983-2020 were analyzed. T1 post-contrast-enhancing disease on baseline MRI was characterized. Site of initial relapse was characterized as purely local (involving/adjacent to initial site) vs distant intraparenchymal, or other (e.g., both local and distant, systemic, ocular). Progression-free survival (PFS) was evaluated using Kaplan Meier methods. RESULTS Of 645 patients, 564 were eligible for analysis (diffuse large B-cell histology, sufficient data, ≥ 1 MRI response assessment). Median follow-up was 2.7 years (IQR 1.2-5.6). Median age was 63 years (range 19-90). Baseline disease was often supratentorial (420, 74%), multifocal (274, 49%), and bilateral (224, 40%). Fewer had leptomeningeal disease (94/430 CSF+, 22%; 117/559 radiographically positive, 21%). Most received methotrexate (MTX)-based induction (534, 96%), most commonly rituximab, MTX, procarbazine, vincristine (R-MVP; 257, 46%) or MVP (144, 26%). Overall, 286 (51%) patients relapsed with a median PFS of 2.1 years (95% CI 1.8-2.5). Of 275 characterizable relapses, 75 (27%) were exclusively local intraparenchymal, 91 (33%) were distant intraparenchymal, and 109 (40%) were other. Baseline unifocal disease often relapsed unifocally (66/118 baseline unifocal; 56%). Of 126 unifocal relapses, 45 (36%) were local. Of 202 patients with baseline supratentorial disease, 152 (75%) relapsed supratentorially. Unilateral relapses often remain ipsilateral (49% left- and 54% right-hemispheric lesions at baseline and relapse). CONCLUSIONS In a large PCNSL cohort, relapses often maintained baseline characteristics. For a disease historically considered multifocal, a substantial proportion of relapses were local. Future analyses will evaluate predictors of relapse, which can further efforts in informing personalization of treatment in the era of cellular therapies.
PATH-13. IMAGE-BASED PHENOTYPING OF GLIOMAS FOR CLINICAL USE
Authors: Aline Becker, Ishya Casukhela, Jany Chan, Joseph McElroy, Tara Eicher, Jessica Fleming, S Jaharul Haque, Raghu Machiraju, Arnab Chakravarti
Journal: Neuro-Oncology (2022)

Abstract Adult-type diffuse gliomas have been classified according to histopathological characteristics only. Based on molecular profiles, the World Health Organization (WHO) classification defines three distinct biologic and prognostic types of diffuse gliomas: (i) IDH wild type (IDHwt), (ii) IDH mutant, 1p19q intact (IDHmut-non-codel), and (iii) IDH mutant, 1p19q codeleted (IDHmut-codel). Gliomas with missing molecular information are classified as “Not otherwise specified” (NOS). A histopathological signature that distinguishes IDH status in gliomas using hematoxylin &amp; eosin (H&amp;E)-stained whole slide images (WSIs) has yet to be developed to be used as proxy for molecular alterations. We employed WSIs with corresponding molecular data from The Cancer Genome Atlas (TCGA) and reclassified the gliomas according to the 2021 WHO guidelines. Weakly supervised deep learning approaches, i.e. the Uncertainty-Aware CNN (UA-CNN), and accompanying workflows developed by our group were successful in the segmentation and classification of other cancers. We used the weak labels of IDHwt or IDHmut for given WSIs and utilized an informative sampling algorithm to identify the most relevant tiles that are predictive of their WSI-level label. Next, a second UA-CNN was trained on the relevant subset of tiles determined from the screening stage. For inferencing, given a WSI, the trained UA-CNN model yielded both a predicted label and uncertainty measure for each tile. When reassembled into a WSI, an aggregated uncertainty classification map is formed, which will allow neuropathologists to more rapidly identify regions of interest. While molecular testing is indispensable for current glioma classification, our tool may help reduce the number of NOS diagnosis, mainly in smaller services, by identifying image features that can differentiate between IDHwt and IDHmut. We expect to develop and deploy a method to increase the amount of information extracted from the H&amp;E stain, and help prioritize downstream molecular analyses mandatory for the layered diagnosis of gliomas.
NCOG-25. THROMBOCYTOPENIA LIMITS THE FEASIBILITY OF SALVAGE LOMUSTINE CHEMOTHERAPY IN RECURRENT GLIOBLASTOMA: A SECONDARY ANALYSIS OF EORTC 26101
Authors: Emilie Le Rhun, Felix Boakye Oppong, Martin van den Bent, Wolfgang Wick, Alba Brandes, Martin Taphoorn, Michael Platten, Ahmed Idbaih, Paul Clement, Matthias Preusser, Vassilis Golfinopoulos, Thierry Gorlia, Michael Weller
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Thrombocytopenia represents the main cause of stopping chemotherapy for toxicity during the treatment of glioblastoma. Here we explored the incidence and prognostic implications of lomustine modification for thrombocytopenia in recurrent glioblastoma. METHODS We retrospectively analysed thrombocytopenia, its consequences for treatment delivery, and associations with outcome in the phase II and III parts of EORTC 26101, a randomized trial to define the role of lomustine versus bevacizumab versus their combination in recurrent glioblastoma. RESULTS 225 patients were treated with lomustine alone (median 1 cycle) (group 1) and 283 patients with lomustine plus bevacizumab (median 3 lomustine cycles) (group 2). 129 patients (57%) in group 1 and 187 (66%) in group 2 experienced at least one episode of thrombocytopenia; 36 patients (16%) in group 1 and 93 patients (33%) in group 2 had their treatment modified for thrombocytopenia. Lomustine was discontinued for thrombocytopenia in 16 patients (7.1%) in group 1 and in 38 patients (13.4%) in group 2. Patients with MGMT promoter-methylated glioblastoma treated with lomustine alone experienced more lomustine treatment modification than patients with tumors without MGMT promoter methylation. On adjusted analysis accounting for major prognostic factors, lomustine modification induced by thrombocytopenia was associated with inferior progression-free survival (PFS) in patients with MGMTpromoter-methylated tumors in both groups, suggesting a link to insufficient lomustine exposure. This effect was noted for overall survival, too, but only for group 2 patients. Patients with MGMT promoter-unmethylated tumors who experienced dose modification for thrombocytopenia had longer PFS and overall survival, and this effect was driven largely by group 2 patients. CONCLUSION Drug-induced thrombocytopenia is a major limitation to adequate exposure to lomustine in patients with recurrent glioblastoma. Its association with survival suggests that mitigating thrombocytopenia to allow enhanced lomustine exposure in patients with MGMT promoter methylated tumors might improve outcome.